In a perfect world with boundless resources, patients would always have access to every doctor’s prescription. But our world is not perfect and our nation is in deep debt. Consequently every day doctors across the country receive denials for medications and procedures that we have prescribed. We know our patients need these medical interventions yet our hard earned positions as practicing physicians (requiring decades of study) are no match for the far less qualified employees of insurance companies. Oftentimes our prescriptions are lifesaving. Yet we are told patients can’t have what we’ve ordered. What we have ordered is simply “too costly”. We are forced to choose something else, even if it is an inferior approach and leaves our patients – those people we have all sworn oaths to protect – relatively unprotected. So, with resources limited to such a degree that we have lost access to solutions we know to be beneficial, what are doctors and patients to do? Let’s look at a disorder deserving great attention and intervention; yet oftentimes remaining hidden in the shadows. The disease is called FH (Familial Hypercholesterolemia) and it occurs in about 1 out of every 200 people.

One of the disorder’s characteristics that makes it difficult to diagnose is the wide variation in how it manifests; some people have LDL cholesterol levels well over 200 (I’ve seen levels over 500) while others are not so badly impacted. Some patients have heart attacks in their teens while others never experience such premature disease. One of modern day medicine’s most well established “facts” is that the lower a person’s LDL, the less likely he or she is to have a heart attack or stroke. Now consider those individuals with FH in whom we simply cannot, no matter how hard we try, adequately reduce their LDL utilizing insurance approved modalities such as statins and dietary modifications. Such people may have already suffered heart attacks at very young ages. They are at extraordinary risk for a future heart attack or stroke. Yet, their insurance carriers still often create impenetrable barriers for access to additional medications as well as LDL apheresis, a method that was FDA approved in the 1990s, and lowers LDL by a whopping 70%. Carriers bemoan the costs of the medications or procedure and cite a lack of adequate “outcome data” as their reason for denial. Though doctors explain that it is now accepted as doctrine by lipid experts across the globe that lowering LDL by any means provides dramatic CVD risk reduction, they remain intransigent. We share our knowledge of Mendelian Randomization studies, which have proved beyond a shadow of a doubt (in the framework of present-day science) that lowering these patients’ LDL levels will vastly decrease their chance of suffering repeated heart attacks, strokes, stents, and bypasses. Still their ears and minds are shut. We, the doctors, are powerless. And our patients suffer the consequences. And, compounding the problem, there is currently active consideration among insurers to make it even more difficult for patients to receive LDL apheresis.

The New Year has just begun and my colleagues and I have already received a plethora of complaints from patients bemoaning the fact that their insurance carriers have increased their medication costs to such a degree that for many they can no longer afford to take them. What will happen to these patients? Will they develop unnecessary heart attacks or strokes? Will they need unwanted and otherwise preventable procedures like bypass surgery and stents? I do worry they will fare less well than had they been permitted to follow the care so cautiously outlined by their treating physicians. And medical evidence does support my concern. I believe an outcry from patients is needed. Doctors will continue to make our case, but until the voices of worried patients achieve adequate volume, I fear the status quo will reign.

“The demands of this poor public are not reasonable, but they are quite simple. It dreads disease and desires to be protected against it. But it is poor and wants to be protected cheaply. Scientific measures are too hard to understand, too costly, too clearly tending towards a rise in the rates and more public interference with the insanitary, because insufficiently financed, private house. What the public wants, therefore, is a cheap magic charm to prevent, and a cheap pill or potion to cure, all disease. It forces all such charms on the doctors.”George Bernard Shaw THE DOCTOR’S DILEMMA: PREFACE ON DOCTORS (1909).

Scientific progress and the tower of babel
Many may have forgotten that Goldstein and Brown originally ascribed familial hypercholesterolemia (FH) to defective 3-hydroxy-3-methyl-glutaryl coenzyme A reductase.(1) The authors promptly corrected their proposition and concluded that a defect in the low-density lipo- protein (LDL) receptor was the basis of FH.(2) Although they had initially been incorrect, their mistake simply illustrated the norm in scientific discovery—and, they won the Nobel Prize in Medicine. Theories are proposed and tested; understanding is honed; and new theories are rewritten. Such iteration is at the heart of progress in science. And, it is a process in need of application by healthcare practitioners worldwide to improve the detection and treatment of people with FH. Specifically, today’s lexicon for FH has evolved to the point of clinical incomprehension.(3,4) Its complexities, ambiguities, and embedded misnomers (e.g., How can double or compound heterozygotes be homozygotes?) will often pose confusion, paradox, and dilemma for the clinician sufficient to impair clinical care; clarification is therefore required.(5–8)

Brief historical perspective
FH was originally defined as a life-threatening auto- somal-dominant, monogenic mutation of the LDL receptor that resulted in hypocatabolism of LDL particles and premature atherosclerosis.(9) Goldstein’s and Brown’s early interpretation of patient data and their use of the Hardy-Weinberg equation for monogenic disorders led to the long held dictum that homozygous FH (HoFH) occurs at a rate of 1 per 1 million, whereas heterozygous FH (HeFH), 1 per 500.(9–11) Unbeknownst to them at the time of their discovery, their scientifically precise definition of the prevalence of HoFH possessed inherent limitations, because it referred strictly to only those patients with a single and same mutation in the LDL receptor inherited from both parents. Now we have come to recognize great phenotypic variability in FH,(12) the worst phenotype being homo- zygous FH determined by the presence of two null alleles in the LDL receptor. Consanguinity additionally enhances the severity of HoFH as evidenced by the founder effects across the world.(10,11) And, many other mutations outside the LDL receptor can also lead to FH.(3,4,11,12)

Evolution of a definition
“HoFH is an infrequent inherited disorder usually caused by mutations in both LDL receptor alleles, which results in very high elevated plasma LDL cholesterol concentrations and very early morbidity and mortality due to accelerated atherosclerotic cardiovascular disease (ASCVD), usually before the patient turns 30 years old. In patients with HoFH, the main cause of mortality and morbidity is the aortic stenosis rather than involvement of the coronary arteries.”(9) This was an original definition for HoFH written by the “fathers” of the disorder. This, as well as the original molecular definition, has itself mutated over the years. FH now includes autosomal dominant mutations in at least two other genes, PCSK9 and apoB 100.(3,4) To further confuse the issue, molecularly defined HoFH now includes both double heterozygotes and compound heterozygotes and may also rarely involve more than two mutations.(10,11) Double heterozygotes possess mutations in two of the aforementioned genes, whereas compound heterozygotes have two different mutations in one of the afore-mentioned genes. Strictly speaking, neither of these entities represents true homozygosity, yet clinically they do result in an HoFH phenotype, albeit with varying penetrance of LDL levels and consequent atherosclerotic cardiovascular disease (ASCVD). For this reason, the newer and less genetically precise terms have appropriately become embedded in our definition of HoFH. This expanded HoFH definition enables doctors to broaden their detection and care of such patients, an extraordinarily high-risk population in need of early and aggressive treatment.13,14 Markedly elevated plasma LDL cholesterol (LDL-C) levels exist even in utero, emphasizing both the genetic nature and very high lifetime risk of ASCVD risk of FH (Fig. 1).(15) Beyond our genetic redefinition of FH, we now recognize the disorder to perturb the entire lipoprotein system.(16) From a metabolic perspective, there is more than just reduced clearance of LDL; there is also coexistent overproduction of apoB, undercatabolism of remnant lipoproteins, and dysfunction of HDL.(16) These extended abnormalities are, however, embedded in the extent of residual LDL re- ceptor activity, which from a metabolic viewpoint could potentially be used to further define FH; however, such molecular testing is not yet readily accessible.(10) As a consequence of the aforementioned diagnostic ambiguities, physicians around the world often face artificial and inappropriate obstacles to optimally manage their patients with HoFH. In the United States, the use of novel agents—lomitapide and mipomersen—are restricted to clinically defined HoFH patients.(17–19) In most countries outside the United States, the United Kingdom, Spain, Japan, and Germany, the use of lipoprotein apheresis is not reimbursed, but if it is, a restricted definition of HoFH is required.(9,10) To enable clinicians to better treat their patients, an improved and pragmatic definition is required for the highest risk FH patients.

Fig. 1 Threshold for ASCVD as a function of cumulative LDL-C exposure. This adaptation emphasizes the genetic aspect of FH, bringing the start point of LDL-C accumulation into the in utero period. Exposure to markedly elevated LDL-C levels occurs even before birth, further explaining the prematurity of ASCVD in such individuals. Additionally the figure introduces the suggested terminology, ‘‘very high-risk’’ and ‘‘high-risk’’ FH. Adapted from Horton JD, et al. J Lipid Res. 2009; 50 (Suppl):S172-S177.

Revision of earlier concepts
Over the past few years, it has become apparent that the current definition of HoFH (expanded from its origi- nal Goldstein and Brown view) is likely inadequate.(11,12) We now have evidence that the prevalence of HoFH may be one in 160,000,(12) whereas HeFH occurs somewhere between 1 in 200 and 1 in 300.(20,21) As noted previously, it is clear that three genes—LDL receptor, PCSK9, and apoB100—mutate and lead to the preponderance of FH cases.(3,4,7,8) There remain some important caveats, however. These estimates of prevalence actually exclude double heterozygotes as well as any potential de novo LDL receptor mutations. Moreover, the new prevalence calculations are approximate estimates of frequencies(12) not being calculated according a multilocus variant of the Hardy- Weinberg principle(22) and without considering population admixture. Additionally, phenotypic analyses in the Copenhagen study show a remarkably large number of patients with severe hypercholesterolemia.(20) It is not clear if this is the result of sharing an unhealthful diet or a high prevalence of inherited disorders, which would suggest genetic isolation.

With regard to double heterozygotes, although the expectation is for them to represent only 5% of the HoFH population, their prevalence in the largest study of geno- typed patients to date was the same as that of compound heterozygotes.(12) Double heterozygotes were removed however from prevalence statistics because such individuals possess a polygenic disorder (two genes to be precise). The authors therefore considered them to be unevaluable by Hardy-Weinberg.(12,22) However, a multilocus Hardy-Weinberg calculation could be performed, bringing a greater precision to the authors’ findings as well as our current understanding of FH prevalence.(12) Because the prevalence of double heterozygotes was much greater than anticipated, and as polygenic mutations are known to remain stable over generations, it is probably inaccurate to exclude these double heterozygotes from Hardy-Weinberg analysis. By doing so, we are left with prevalence estimates that fail to account for double heterozygotes with phenotypic or clinical HoFH.(3,4,23)

There is also the issue of typically requiring both parents to have either very high LDL or premature ASCVD to meet clinical HoFH criteria.(10,11) Two notions could argue against this requirement. First, there is the possibility of de novo mutations. Although little is known specifically about the incidence of de novo LDL receptor gene variants, we do know that this gene can be subject to many mutations.(4)

Recently, whole exome sequencing for the evaluation of other Mendelian disorders revealed a surprisingly high incidence of 83% de novo mutations in autosomal dominant disorders in the population assessed.(23) More than 1700 genetic variants in the LDL receptor have hitherto been identified (not all of which are pathogenic, however). Such a high prevalence of mutations in the LDL receptor does raise the question of whether or not it can also be subject to de novo mutations.(7,23) Second is the issue of nonpaternity, a very challenging matter in a clinical setting.(8) Nonpaternity occurs when the presumed father of a child is not the biological father and is rather frequent with estimates between 0.8 and 30%.(24) Further confounding the assessment of true HoFH is the fact that genotyping itself, probably owing to technical limitations in the main, is imperfect. It is far less sensitive than we would like. Estimates are that somewhere between 20% and 70% of patients manifesting as phenotypic or clinical possible to definite FH (HeFH and HoFH) can be overlooked through current genetic sequencing techniques.(7,8,25–27)

Communities subject to gene founder effects aside,(23) it therefore appears that the figures cited previously for the population prevalence most likely underestimate the true frequency of HoFH. HoFH, as expressed clinically, is therefore not only far more common than we previously considered, but it could be even more common than we are presently led to believe. Making matters more perplexing, we now have documentation of pathogenic mutations causing HoFH yet resulting in an untreated LDL-C as low as 170 mg/dL.(12) Such a low LDL challenges prior criteria for HoFH, many of which stipulated an untreated LDL-C .450 mg/dL (and treated LDL-C .300 mg/dL) in the HoFH individual.(10) An untreated LDL-C of 170 mg/dL not only breaches the current HeFH boundaries, but even overlaps with polygenic or common hypercholesterolemia (Fig. 2). Contributing to current scientific uncertainty and clinical ambiguity, polygenic mutations can sufficiently elevate plasma LDL-C to mimic FH.(26,28) Given the emerging new knowledge of the prevalence, phenotypic expression, and genetic etiology of FH, coupled with the recognition of our inability to clinically and even genotypically distinguish the heterozygous and homozygous entities, why make an arbitrary distinction between HeFH and HoFH?(10–12) We currently do not have the capacity to be scientifically precise in making this distinction. Therefore, from a practical perspective, we must either revise our definition of HoFH, or abandon the notion that such a definition should take a primary position in the clinical decision making process. Because a clinically pragmatic revision of the definition will only take us further from the true genetic meaning of the term, it might be best simply to acknowledge that the definitions of HoFH or HeFH should have a diminished role in the clinical management of patients after the diagnosis of FH has been made. Our view is that the phenotypic expression of the disease should drive the patient-centered therapeutic strategy.

Meeting the challenge with a clinical solution: improving the utilization of novel therapiesBy early 2013, two novel agents, lomitapide and mipomersen, were approved in the United States as adjunctive therapies for patients with HoFH aged $18 years.(19,29) Because HoFH is by definition an orphan or rare disease (affecting fewer than 200,000 people in the United States, or less than 1 in 1500), the Food and Drug Administration’s evaluation of these medications differed substantially from their standard pharmaceutical approval process. Additionally, orphan medications are exceedingly expensive, often more than $200,000 per patient per year. Thus, to prescribe these medications, physicians must attest that the patients for whom they are prescribing the drug meet the criteria for the given rare disease, in this case HoFH. Specifically, a prescribing doctor must state, ‘‘I affirm that my patient has a clinical or laboratory diagnosis consistent with HoFH’’.(29) In other words, a necessary barrier has been constructed to prescribing orphan drugs. Herein lies the specific major issue though. As argued previously, the demarcation between HeFH and HoFH can be challenging on both clinical and genetic grounds. Consequently,FH—including HoFH—is grossly underdiagnosed and similarly undertreated. It is estimated that less than 1% of FH patients in the United States have been adequately diagnosed.(7) Reeducation is in order; teaching medical practitioners to have FH as a fixture on their differential diagnostic list of LDL disorders is crucial.(5–8) Equally pressing, however, and of immediate concern in the United States, is the quandary of when to prescribe these novel medications to our patients, acknowledging also the lack of clinical endpoint trials, which for ethical reasons will never be undertaken.(19) It would be simple if the issue were clear-cut. This is far from the case, however, and can present the treating physician with a challenging clinical dilemma. Doctors must acknowledge the difficulties inherent in distinguishing HeFH from HoFH, but still determine whether a given patient presents with a clinical phenotype that is consistent with HoFH. Because FH can be a lethal condition in either heterozygous or homozygous forms our approach should be driven by the clinical manifestations of an individual patient’s specific, causative molecular or genetic defect.

The doctor’s dilemma resolved with a common language strategy: a pragmatic approach to managing clinically severe FH
We proffer the following clinically grounded approach that may simplify and enhance the care of adult patients with clinically severe FH, regardless of its genetic bases (Fig. 3).

Triage using established clinical tools
A family history of premature vascular disease, a marked and often isolated elevation of LDL-C, premature and/or aggressive vascular disease, a limited response to lipid-lowering therapy, and the presence of physical stigmata of FH must all be considered.(5–8) If, based on these considerations, there is a strong suspicion of FH, either the Simon Broome or the Dutch Lipid Clinic Network criteria should be employed.(5–8) Worldwide, the Dutch Lipid Clinic is more commonly used because it is considered more sensitive than Simon Broome.(7,8) Although it is commonly considered the system of choice to help clinicians diagnose FH (7,8) in Western populations, in other countries alternative criteria should be employed.(21,30) MEDPED is excluded here because its system hinges solely upon LDL-C levels and strictly requires knowing LDL-C in several family members.(31) In our opinion, this tool also bears ambiguities that may be confusing when cascade screening to detect new family members with FH. It is important for clinicians to recognize that LDL-C levels differ between the sexes and steadily rise through life.

Fig. 3Novel care pathway for identifying and treating patients with FH. In view of the recently recognized wide genetic and phenotypic variability of FH, this algorithm is intended to simplify and improve care of patients with this disorder. The algorithm shifts the impetus of therapeutic intervention choices from genetics to phenotypic/clinical expression. The individual patient with his or her unique manifestation of disease is emphasized.

Thus, an LDL-C adjustment should be contemplated when calculating the likelihood of FH, particularly when there is a family member with documented FH.(32) If patients do not meet FH criteria when assessed with the Dutch Lipid Clinic Network, they should be treated according to current lipid and cholesterol guidelines.(33–36)

Assessing ASCVD and an inadequate response to treatment
With severe/progressive ASCVD, or a clinically significant degree of subclinical disease, and probable or definite FH,(7,8) the patient could be considered to have a condition termed ‘‘high-risk FH.’’ Every effort using standard therapies should then be made to drive the LDL-C below 70 mg/dL.(6–8) Lipoprotein a (Lp(a)) should also be assessed.(37) Lp(a) is a potent, independent risk factor for coronary events in FH and an assessment of its plasma concentration and allelic size therefore has been incorporated into this protocol.(38) Very high plasma Lp(a) concentrations may mandate earlier introduction of lipoprotein apheresis (39–41) or, when available, apolipoprotein a antisense therapy.(16) If the level is $50 mg/dL, regardless of the LDL-C level, lipoprotein apheresis should be initiated. If an aggressive attempt to reach an LDL goal ,70 mg/dL is unsuccessful, the patient should be considered to have ‘‘very high-risk FH.’’(42) This classification would emphasize the urgency and concomitantly augment the intensity of treatment. Although ‘‘very high-risk FH’’ might include both patients with severe HeFH as well as those with severe HoFH, the US Food and Drug Administration attestation for the two novel agents lomitapide and mipomersen (17,18) could be satisfied on clinical grounds. Such a classification system is reasonable given our recent understanding of the greatly overlapping spectra of HeFH and HoFH. Both lipoprotein apheresis and/or these novel medications must be seriously considered in very high-risk individuals with FH. As further evidence for the efficacy and safety of PCSK9 inhibitors in severe FH grows and other therapies,(18,43,44) such as the CETP inhibitors, potentially achieve their clinical endpoints, the algorithm may be applied to these agents as well.(11)

Managing the FH patient free from ASCVD
In the absence of significant vascular disease (e.g., prior ASCVD event; peripheral artery disease; obstructive carotid artery disease; coronary artery calcification $75% forage/sex; coronary artery calcification $300; or a large burden of soft plaque or multiple plaques noted on coronary computed tomography angiography), the patient should be managed aggressively with conventional approaches, including therapeutic lifestyle changes.(7,8,34) Follow-up evaluation with imaging studies is recommended. The review intervals should be determined on clinical grounds, perhaps ranging from every other year to every 5 years. The frequency of imaging will depend on the severity of the patient’s residual LDL-C elevation as well as the initial degree of any vascular disease.(11,45,46) The key is to very aggressively manage those FH patients with poor prognostic indicators. Comorbidities such as tobacco abuse, hypertension, diabetes mellitus, and a markedly elevated Lp(a) should also be aggressively treated when possible.(7,8,11,33–37)

Reflections on the algorithm
At present, physicians must accept our inability to be certain of the exact genetic etiology of FH in patients in whom they have made a well-considered clinical diagnosis of the condition. Likewise, physicians practicing in the United States must not fear the attestation required to prescribe the aforementioned novel medications for FH. This is not a proclamation of the incontestability of the diagnosis of HoFH. The attestation simply states that HoFH remains solidly on the differential diagnostic list. The pragmatic solution that we propose is likely to widen use of novel medications and lipoprotein apheresis. However, their enhanced use is compatible with best clinical care for a condition that inadequately treated bears a uniquely high risk of ASCVD.(13,14,47)

It is also true that ASCVD outcome studies have not been performed with these novel agents, and their long-term safety has yet to be demonstrated.(19,48) Still, it is reasonable to infer emergent significant risk reduction when this highly at-risk population experiences LDL-C reductions of 25 –50% and greater.(8,11,13,14) Additionally, the proposed algorithm could be readily tested with large cohorts of FH patients, for instance within the context of national and international registries.(49,50) For example, patients defined in the proposed clinical algorithm should be incorporated into the ongoing registry, CASCADE FH. Through CASCADE FH, real-world cost/benefit analyses will become possible. Though the cost of more prevalent drug therapy and lipoprotein apheresis would be problematic, it is not unreasonable to assume that the increased use and effectiveness of these therapies could concomitantly drive down their costs. Included in such a cost analysis (which is beyond the scope of this article) must also be considerations regarding the costs averted by the prevention of ASCVD as well as the improved quality of life from prevention of clinical events and indirect cost savings to society.(13,14,51,52)

A biochemical distinction that may bear on the response to new therapies, particularly with PCSK9 inhibitors,(43,48) has been previously made among patients with severe FH on the basis of residual LDL-receptor functional activity measured in skin fibroblasts.(53) The notion of including such a measurement in the clinical assessment and triaging of patients has appeal, but the technical complexities restrict its application to research settings alone. Additionally, the skin fibroblast, having no role in maintaining our body’s cholesterol homeostasis, may not be the best model on which we should base clinical decisions. Plasma PCSK9 levels vary with LDL-C concentrations,(54) but whether this measurement has a role with clinical management of patients remains unclear.

Finally, the algorithm does not include children, but in this age group the diagnosis of ‘‘high-or very high-risk FH’’ may also be readily made on clinical grounds.(8,10,11) Guidelines recommend that all children with suspected FH be screened with measurement of LDL-C with or without a test for the family mutation, if known, by age 2 years and treated aggressively, including as indicated lipoprotein apheresis, by age 5 years and no later than 8 years.(8,11) There is very limited experience with the new therapies for lowering LDL-C in children. However, children deemed to have high risk FH could enter the algorithm at the stage of confirming subclinical ASCVD and/or aortic valve disease.(8,11)

Baum Challenges in HFH diagnosis and care

So is there a role for genetic testing in the care of FH?
The detection and management of FH includes the entire family. Cascade screening of close family members is part of our duty of care and, resources permitting, this is where there is an important role for genetically testing of index cases to identify the pathogenic mutation/s causative of FH.(5,8,55)

Genetic testing is most unlikely to alter the management of the index case once the clinical diagnosis has been made, but it can certainly make cascade screening more cost-effective and can especially increase the accuracy of diagnosis in children.(52,56–58) The treatment of severe FH in children, although outside the scope of this article, needs to be addressed along similar lines as the pre- sent proposal.(8,11,15,59,60)

Conclusion: enhancing the model of care for severe FH
The physician’s role is to offer each and every patient the best possible standard of care. This is the foundation of the modern era of patient-centered medicine. Instead of grappling with a diagnostic distinction we currently clearly cannot resolve, the time is ripe to focus attention on detecting and appropriately treating the entire spectrum of FH patients in dire need of current best standard of care. Risk stratification and identification of the most severe of these patients should be based on their phenotypic, not genotypic diagnosis, although a genetic diagnosis may be useful in cascade screening families. Patients who have ‘‘high-risk FH’’ or ‘‘very high-risk FH’’ are at extremely high peril of progressive and life-threatening ASCVD. Recalling the adage that inspired an accelerated speed of treatment during the early thrombolytic days, ‘‘time is muscle,’’ we now can use a comparable dictum for this type of FH patient. These individuals share time urgency. Most definitely for them, “time is plaque.”

Future considerations also include the following: improved biochemical typing of the severity of FH and the response to therapy, such as PCSK9 inhibitors, would require the development of simple, precise, accurate and practicable methods for assessing residual LDL-receptor function. Novel imaging methods for detecting inflammation in unstable coronary plaques (61,62) as well as genetic tests to assess individual susceptibility to the side effects of existing (63) and new therapies for FH could in the future be incorporated into the clinical care pathway.

Finally, the algorithm presented is based on our own personal experience of managing caseloads of patients with severe FH who have presented us with clinical challenges and dilemmas. We acknowledge that the proposition is based on expert opinion and therefore constitutes a view- point that requires future testing. It should also be noted however that all guidelines concerning management of HoFH are mainly based on expert opinion (European Atherosclerosis Society/European Society of Cardiology; National Lipid Association; American Hospital Associa- tion/American College of Cardiology; National Institute for Health and Care Excellence; International Familial Hyper- cholesterolemia Foundation). We have remained within current guidelines for FH diagnosis and expanded our therapies in response to our growing understanding of the wide range of FH phenotypic expression as well as clinical predictors of higher risk. The care pathway proposed is a nonprescriptive living document, and as such will need to be investigated and further evaluated, including assessing its effectiveness, utility, and cost-benefit. This is necessary to revise and enhance the protocol and to also allow the incorporation of novel diagnostic and therapeutic capabilities referred to previously that need evaluation in their own right. The algorithm, however, offers clinicians a simplified and pragmatic pathway for more effectively managing high-risk FH patients and lays a new foundation for improvements in international models of care for FH.

It is juvenile to make wishes and even more so to believe they might come true. It is especially puerile for me to hope that my particular list of holiday wishes will actually come to fruition. But it is that time of year when we permit ourselves a degree of fantastical thinking and a smidgen of youthful optimism. So here are my dreams:

1. I want to see the return of honesty. I await the day when people will be truthful in their deeds and words. This requires deep self-reflection on all our parts so when we say or do something we come from a place of hard-earned sincerity. An example would be the current protests of “rampant police racism” culminating in the execution style murder of two innocent officers. Did rampant racism really cause the two recent incidents that have ignited the fury of those promulgating the racism story? No: No evidence supports that thesis. The police have done far more to protect blacks than to harm them. Thus, the recent riots and murders are the result of some other underlying frustration. It is that hidden root of this discord that must be revealed. Those involved in the frays are the only ones with the capacity to acknowledge the misplaced anger of rioters and murderers. My hope is that prominent and powerful leaders will help, not hinder the process of revelation.2. I want to watch an unbiased mainstream news report. An old-fashioned report sans biases and fears of reprisal; emphasizing primary sources – not speculative and oftentimes-mindless meanderings – would provide the people of our nation with what we deserve. The media owes it to Americans to find and share the facts. A healthy dose of truth would be most welcome.3. I’d love to see the recent surge in racism quelled, not fueled. Since the 60s we have made monumental strides in eradicating bigotry and advancing the opportunities available to African Americans. Just look at our current political landscape – a Black President and Attorney General along with 10% of the House of Representatives. Such a landscape would have been unimaginable 40 years ago. We have surely come a long way. Black doctors, lawyers, business people, and newscasters are no longer an anomaly. They are very much the norm. So why now do we suddenly all feel so racially divided? I want an end to the divisiveness. As an aside I can safely say that almost all Americans have experienced the sting of prejudice. As a Jew I have. The way to conquer such antiquated beliefs is by succeeding. Becoming successful and productive, and contributing meaningfully to society goes a long way to eradicating misconceptions that are the root of prejudice.4. I pray for unity in thought and action among those of us who treasure individual rights and freedoms above all else. Let’s end the politically correct attempt to establish moral equivalency among nations and individuals embroiled in battles for survival. With regard to the Israeli/Palestinian conflict let’s not equate accidental deaths of children from Israeli strikes needed to dismantle hostile and active missile launch sites with intentional Hamas attacks on innocent women and children. The same holds true for mass murders of children in Pakistan and other nations. There is absolutely no excuse or rationale for intentionally killing children. We must put aside our political positions on this and similar issues. We must remember that right and wrong do exist. As a world we must condemn wrong actions, regardless of our particular political views.5. I yearn for unity in condemning the brutality of Muslim extremists. That means Muslim non-extremists, Christians, and Jews must stand as one and fight our anachronistic and growing foe. This requires real and continual action on the parts of individuals, groups, and Nations. Beheadings, limb amputations, rapes, kidnappings, forced conversions to Islam, public assassinations, and crucifixions have no place in the 21st century. They should be snuffed out with the same vehemence from whence they sprung.6. I pray for a way to aid less fortunate Americans: To help the poor and disadvantaged rise and succeed without diminishing the positions of those who have already struggled for success. Leveling the playing field should not require damaging those who have already succeeded. It should be done by enabling those who wish to succeed find a means to do so.7. I’d like to see an end to ad hominem attacks on politicians during political campaigns. Let’s hear what politicians truly believe; let’s have the opportunity to understand their visions and plans for implementation. Let’s avoid bringing them down through false character assassinations and the like.8. I’d like to see a functional government; one that values its constituents more than it does itself. This would be a government run by people who remain honest, support the views of Americans, build America up, think toward the future, and leave office when they can no longer help those whom they represent.9. I pray for America to regain its position as the world leader. We led not only as an economic force, but also a consistent moral compass. We have relinquished that role and now a void has formed. Voids these days tend to be filled by those who do not share our evolved values and beliefs. Let’s regain our primary position in the world before another less enlightened entity takes the world’s reins.10. Finally I hope for the day when we will unify under an American leader who delivers a President Kennedy type message that resonates with all Americans, “Ask not what your country can do for you, but what you can do for your country.” We all need to hear and feel that again.

Any doctor worth his salt recognizes that patients don’t always respond the way we anticipate they will. For example, utilizing the best of our scientific methodologies we know LDL is causally related to vascular disease. High LDL causes disease while low LDL mitigates it. Yet, we occasionally see patients with extraordinarily high LDL and no disease, as well as those with very low LDL and severe disease. In some circumstances, patients with a vascular disease promoting mutation – as in Familial Hypercholesterolemia – will have severe and premature heart disease while their relatives with the same mutation somehow remain unscathed. How can this be? What we’ve all come to believe is that there must be protective genes that somehow offset the detrimental aspects of other genes. Let’s dub these desired genes “Guardian Genes”.

In the case of vascular disease promoting disorders, Guardian genes cause the exception, not the rule. They Teflon coat individuals who under normal circumstances should develop heart attacks and strokes. This wonderful rarity can unfortunately lead to a misunderstanding of disease processes as well as their cures. When someone speaks of grandma whose LDL was 300 and yet lived to the ripe old age of 100, sans MI or stroke, the take-home message often is, “Those doctors don’t know what they’re talking about. LDL is not the cause of heart disease. My LDL is only 200 and as grandma lived to 100 and with worse numbers, why should I take that statin medicine. Just look at the Internet and you can see how terrible those medicines are.” Unfortunately the Guardian genes are currently merely speculative. As such we cannot identify them. And, we know that intra-family variability in development of vascular disease supports the notion that theses guardian genes are inherited entirely separately from the disease promoting genes. What that means is just because grandma won the lottery, don’t bet your life (literally) that you did as well. In my own practice I’ve seen 70-year-old parents mourn the deaths of their 40-year-old sons and daughters who died of MIs. Though they shared the same bad genes, the parents did not suffer the unfortunate (and more predictable fate) of their children.

The bottom line here is that we doctors must base our treatment recommendations on the odds. We weigh and measure the pros and cons of therapeutic options (like the statins) against the likelihood that an individual patient will develop a serious event such as a heart attack, stroke, or even death. We use our best judgment based upon many facets of knowledge and understanding. We then make our recommendations hoping to stave off future adverse cardiovascular events. We never risk a patient’s life hoping he or she has inherited a guardian gene. Until we identify the elusive lifesaver guardian genes they will remain relegated to being the modern day Holy Grail of genetics. We all pray we will find them, but until that day we must continue to practice within the limits of our understanding. And while we do, we hope our patients understand that our suggestions and recommendations are born of both a deep understanding of the science of medicine and the burning desire to help our patients live the longest and best lives possible.

I know I’ve written about this issue before – and I guarantee I will write about it again – but I assure you it is important enough to be discussed until even after it has been resolved. The Randomized Controlled Trial (RCT) has become something greater than life. It is the foundation of all Guidelines; it is the subject of Board test questions; it is the trump card in all roundmanship controversies. RCTs have taken on a power beyond all other aspects of medical knowledge. And I am sure this fact represents one of Medicine’s most perilous errors. Instilling RCTs with veto power across all lines of medical debate has relegated such things as clinical acumen, understanding of pathophysiology, and good old-fashioned common sense to second-rate skills. Endowing the RCT with omnipotence has all but eliminated the need for doctors and other health care practitioners to read extensively and understand the fundamental principals of medicine. Two recent examples plainly illuminate this problem.

In one case, a woman with a history of breast cancer as well as ASCVD finished her fifth year of Arimidex. Should she continue was the question, even though the medication might have been making it more difficult to effectively manage her lipids. No study had resolved this issue and so she decided to discontinue the medication. Troubled by her decision I contacted her oncologist and asked him what his gut suggested we do. He favored continuation of the medication. We listened to his well-honed instinct and simply fought a bit harder to control her cholesterol. Last week she was one of the first to have a test to predict the value of Arimidex continuation beyond year five. It turns out that she has a very high risk of breast cancer recurrence in the absence of drug. In other words, the oncologist’s gut was spot on. Perhaps the decision saved her life.

In another case, a friend recently told me that since our conversation regarding his atrial fibrillation four years ago – when I had suggested he stop drinking seltzer and also increase his magnesium intake – he completely stopped experiencing episodes of Afib. At the time he was having such frequent bouts of arrhythmias that radiofrequency ablation was strongly advised by all his physicians. Fortunately he tried an unproved treatment (which I, an electrophysiologist, had seen work in other patients) and it was entirely effective. By trying something safe yet unproved, he was spared a potentially life-threatening procedure.

Reflecting on how we all practice medicine, I cannot but acknowledge the fact that most of our decisions are based upon data distinct from what can be found in the RCT. The bottom line: let’s respect and honor that which makes doctors more than just a commodity – our knowledge, instinct, clinical acumen, common sense, and sometimes our depth of caring.

The AHA 2014 Scientific Sessions are over and I have already written twice about IMPROVE IT but I feel compelled to write again. Although the media has been oddly silent about the trial (why is that I wonder???), I predict its fallout will greatly impact the disciplines of Cardiovascular Disease Prevention, Clinical Lipidology, and even the essence of clinical practice. The reasons are manifold. First, the trial proved two critical theories: a lower LDL cholesterol level is better, and statins are not the only way to achieve a clinically relevant LDL reduction. Additional key considerations from IMPROVE IT include:

Lower LDL in properly chosen patients (and probably almost everyone) yields lower rates of stroke and heart attack, the two most formidable foes of modern man. For example, in the trial, an LDL of 53 was significantly better than an LDL of 70. Should we doctors then aim for 40, or perhaps even 25?

In our high-risk patients should we consistently and continuously add medications to statins in order to drive cholesterol levels lower and lower? For example, in a patient with a prior heart attack is it now fair to accept 70 for an LDL when we know that 53 would decrease our patient’s chance of having a recurrent and potentially life-threatening event?

What do we do with the hotly debated 2013 ACC/AHA Cholesterol Guidelines? They eliminated LDL goals and allowed for the use of Zetia only with individualized – and typically time-prohibitive – clinician/patient discourse, but they did NOT encourage driving LDL lower than 70. The Guidelines advocated for an LDL response to therapy of > 50%. So where does that leave our heart patients who start with LDLs of 180, for example. If they achieve the intended LDL reduction of 50% and thereby remain with an LDL of 90 mg/dL the guidelines surely say all is well – job well done. They state there is no indication to go further. Well now there is an indication. Now we can say with certainty that an LDL of 53 is a far better goal than 90. Having an LDL of 90 leaves significant and now manageable residual risk. So then how can a health care provider in good conscience advocate keeping such a patient at an LDL that clearly conveys greater risk?

The Guidelines also strongly advocate our utilization of maximum statin doses prior to adding an agent like Zetia. Knowing that higher dose statins produce more side effects while yielding a diminishing return on cholesterol lowering, wouldn’t it now be more prudent for doctors to prescribe low dose statins in combination with Zetia? This would limit side effects while yielding lower LDL levels than would the Guideline recommended approach. More food for thought.

How will insurance providers respond to Improve-It’s results? After the ACC/AHA Guidelines’ release, with lightening speed they downgraded access to add-on therapies such as Zetia. Of course that saved them money. So what now? Will they respond in kind, follow the science, and quickly allow patients access to these medications? We shall see but I have my doubts. Profits it seems oftentimes take precedence over science and health.

One more crack at the Guidelines for now: It is true that we do not know what represents the optimal LDL cholesterol level in human beings. Based upon our ever-expanding understanding of lipids including our body’s limited need for extraneous cholesterol however, it is safe to say that that level is probably quite low, perhaps even as low as 25 or 30 mg/dL. And, given the fact that many of us are goal-oriented, wouldn’t it now make sense to join our friends across the pond as well as our very learned friends here at home in the National Lipid Association and simply reinstate LDL goals?

As I sit at my desk tapping these keys I am clearly frustrated by the politics and economics woven inextricably into the fabric of medical practice. But I am also comforted and encouraged by the knowledge that many of us have already spent the last decade and beyond practicing the way we felt the science dictated. And by so doing, in the matter of LDL-lowering with Zetia, for every 120 patients we’ve treated in an Improve-It style, we’ve saved 3 from enduring a stroke or heart attack. This fact renders all our struggles worthwhile.

On a final note let us not forget that doctors have NO financial incentive to prescribe these medications. Our only “dog in the fight” is protecting our patients from harm. Insurance providers often do have a financial incentive to preclude doctors from prescribing some medicines (typically those that cost them more money). So whom do you, the patients, want to be in control of your medication regimen – the more highly educated and clearly non-conflicted physicians, or the less knowledgeable and often-conflicted insurance carriers? The answer to me seems pretty clear.

The IMPROVE-IT verdict is in and it will change the practice of cardiovascular disease prevention. For the first time, a non-statin medication has been shown to reduce cardiovascular events (including stroke and MI) when added to a statin. Achieving an LDL level of 53 vs 70 by the end of the trial’s first year translated into a significant ASCVD risk reduction. The risk reduction is so substantial that in this patient population the “number needed to teat” was only 50. That means that for every 50 patients treated with Zetia on top of a statin, a serious/life-threatening event was prevented. And, there were no safety issues associated with adding Zetia. Thus, a downside was not present. There are so many ramifications of this trial; I will highlight a few:

As believed by most lipid (cholesterol) specialists, lower LDL is definitely better.

Many insurance companies will have to revisit their denials of Zetia – it has now been shown to be highly effective and must be a part of doctors’ armamentaria.

Other emerging medications that dramatically lower cholesterol – the PCSK9 inhibitors and possibly the CETP inhibitors – will likely lower ASCVD events in the right patients.

In patients with severe genetically caused high cholesterol – specifically those with Familial Hypercholesterolemia – doctors will try even harder to use varied tools to lower LDL as much as possible. This includes using LDL apheresis, a procedure that has frequently been denied coverage by many insurance carriers, even after experts have testified about its efficacy.

We have learned that an understanding of biology and pathophysiology, in the context of clinical experience and careful observation, should not be dismissed solely because of the absence of a large randomized controlled trial (RCT). Though it took an RCT to prove this point, those of us who have been using Zetia religiously for many years have borne witness to its efficacy. We did not need this trial to tell us how important the medication is in the management of ASCVD, but it surely makes us feel better (and a bit vindicated as well). Most consequentially, it is heartwarming to consider the vast numbers of patients we’ve helped avoid experiencing heart attacks and strokes as a result of our well-considered and steadfast convictions.

Tomorrow morning a large crowd will gather here at the AHA meetings in frigid Chicago to learn the findings of the long-awaited IMPROVE-IT trial. The trial will demonstrate whether or not Ezetamibe (Zetia) added to a Simvastatin (Zocor) successfully decreased cardiovascular events in high-risk patients.

Many lipid specialists and cardiologists, myself included, have used Ezetamibe in combination with statins since the drug’s release. We believe wholeheartedly in the “lower LDL is better” hypothesis. Our clinical results, though anecdotal, have been uniformly exceptional. We fully anticipate that – barring confounding circumstances – the trial will be a winner.

Making this prospect even more impactful is the current NEJM publication by Dr. S. Kathiresan, (a brilliant Harvard Cardiologist/Geneticist) describing a novel genetic mutation that decreases LDL cholesterol, and concomitantly reduces ASCVD events. Where is this mutation you might ask: In the same receptor that is blocked by the drug Ezetamibe. Essentially individuals bearing such a mutation are born with the equivalent of continual Zetia use. This experiment of nature surely supports the speculation that Ezetimibe effectively lowers heart disease, even on top of statin therapy.

For now, we can only speculate about IMPROVE-IT’s findings. Tomorrow will bring some hard facts along with an assessment of how the findings will impact not only doctors’ use of Ezetamibe, but equally importantly, how health insurance companies will view the matter as well. Until tomorrow my admittedly unbiased fingers will be tightly crossed.

Last week’s The Voice brought us a superb rendition of the timeless song Mad World which emotionally depicts collective adolescent angst. Mad World to me however conjures feelings about our modern world, besieged by increasing racial and ethnic strife, both of which are continually fueled by those who should instead be squelching the consuming conflagration. Writing a blog limits my ability to comprehensively analyze this issue so I will mention just two problems that clearly are being fueled by either the ignorant or the malevolent.

The first is racial division. No one can honestly deny the growth of this destructive force. Many examples could be cited and hypotheses rendered but watching the news last evening I was struck by a single worrisome observation. Apparently the upcoming senatorial elections are not only consequential, but also nail-bitingly close. So both sides are doing whatever they can to mobilize their troops to vote. It certainly makes sense to do so. What struck me though was listening to African American Democrats at all levels of power emphasize the need to mobilize the black voters. The black vote they say is nearly uniformly Democrat and therefore they must encourage them to vote. What strikes me is the notion that African Americans are being bundled into a singular stereotyped group by those Blacks currently holding elected office. Are ALL Blacks really the same? Shouldn’t Blacks be recognized to have disparate views independent of their skin color? I know Black doctors, lawyers, engineers, scientists etc. Are we to believe they all hold the same political stance? The answer of course is no; they do not. Imagine if you heard the white politicians calling Whites out to vote – the notion would not only offend Blacks and Whites alike; it would also be terribly misguided. So, how do the African American politicians calling for Blacks to vote not see they are marginalizing the Black Race? If I were Black, I would be appalled by their supplications. I would also recognize their actions to foster, not fix racial divisiveness.

The second issue concerns growing Anti-Semitism. Recently a relative called me to express her concern about a bumper sticker saying “Boycott Israel”. There are so many examples of Anti-Semitism here and abroad, some restricted to verbal abuse, others physical. Let’s just look at the Boycott Israel notion. I would suggest that anyone supporting such a stance should lead by example. That would mean you couldn’t have a colonoscopy as the Israeli’s invented the camera used in that procedure. You couldn’t have a capsule endoscopy – they invented that too. If you have Multiple Sclerosis you’d probably have to abandon your medication and if you were a paraplegic you’d have to abandon your device that helps you walk. Yes, the Israeli’s invented those medical marvels too. If you like your flash drive; oops, that’s got to go; and if you like text messaging, sorry you better stop – Israeli’s again. The list of Israeli inventions is nearly endless and if you add Jewish inventions you might as well stay home and raise your own food and build your own appliances. In fact, you won’t be able to go shopping at all because a Jew invented the barcode. The point is that before you spew racial or ethnic derision, get educated. Know what you’re talking about and if what you’re saying is based solely on bigotry; try staying silent.

On October 13th the world’s “who’s who” in FH research and patient care convened in an oddly elongated New York City hotel meeting room. For two days the group shared novel information, spontaneous ideas, well-conceived proposals for future research, and even heart wrenching stories from a handful of brave and resilient FH patients. Windowless room notwithstanding, leaders from the Netherlands, South Africa, Australia, Chile, Russia, France, Sweden, Oman and the US uniformly basked in the bliss of a mutual goal, raising awareness and improving treatment for this far too common and oft-unrecognized disease.

Some of the highlights included a one-year review of the FH Foundation’s CASCADE FH Registry. We were all pleased and proud to learn that the Registry had surpassed its forecast goal by over 30% (Actually by over 400% of a more modest prediction). We travelled the world identifying FH “Gaps Across the Globe.” During this session leaders from diverse nations compared and contrasted barriers to care, offering useful methods to hurdle such obstacles. We heard from a continuum of clinicians – internists, lipid specialists, endocrinologists, cardiologists, and gastroenterologists – as well as PhDs occupying a wide range of disciplines. To say the conference was comprehensive fails to express its exceptionality. It was a time apart from other times, a transcendent growth opportunity for all those fortunate enough to be in attendance. It will surely serve as a solid springboard for meaningful clinical collaborations throughout the next year.

In sum, the 2014 FH Global Summit was so spectacular it will be hard to surpass in 2015. However, considering the passion and energy shared by members of the FH Foundation and colleagues across the globe, I feel safe in predicting that 2015 will exceed even the extraordinariness of this year’s event.